Human sense of taste is believed to be constituted of five basic tastes—salty, sweet, acidic, bitter and umami taste (relishable taste). Each taste is generated by the binding of a taste substances to each receptor specifically expressed in taste cells existing in taste buds of the tongue. Until now, ENaC/Deg. (salty taste receptor), EnaC, ASIC, HCN (acidic taste), T2R family (bitter taste receptor), T1R2/T1R3 (sweet taste receptor), Taste mGluR4 (umami taste receptor), etc. have been cloned as candidates of the taste receptors (As to details, refer to Lindemann, B., Nature, 413; 13, 219–225, 2001; the cited document is incorporated by reference in the present specification; that is the same hereinafter as well).
A low-affinity glutamate receptor expressed in taste bud cells in the rat found by Chaudhari, N., Landin, A. M., Roper, S. D., et al. as an umami taste receptor has been a convincing evidence for proving the umami taste-receiving mechanism at molecular level (Nat. Neurosci., 2000, February; 3(2):113–9). The umami taste receptor has the same host gene as that in type 4 (mGluR4) which is a subtype of glutamate receptor of a rat brain type/a metabotropic type (Tanabe, Y., et al., Neuron, 1992, January; 8(1):169–79; Flor, P. J., et al., Neuropharmacology, 1995, February; 34(2):149–55); and since taste type mGluR4 holds a partially deficient extracellular domain by a splicing variation, the finding of specific working substances other than glutamic acid that can utilize the present new type variant as a peripheral glutamate receptor has been receiving public attention.
Glutamic acid is a major excitatory neurotransmitter in the central nervous system, and it is widely accepted that its abnormal control is involved in progressive encephalopathies such as memory disorders, ischemic encephalopathy, amyotropic lateral sclerosis (ALS), Parkinson's disease, and Huntingon's chorea (Meldrum, B. S., Neurology, 1994 November; 44 (11 Supple 8):S14–23; Nishizawa, Y., Life Sci. 2001 June 15; 69(4):369–81). Therefore, many studies concerning glutamate receptors have been carried out up to now in cranial nerve system. Many receptors (three kinds of ionotropic receptors and eight kinds of metabotropic receptors) have been found in the central nervous system with their splicing variants as well. Particularly, since 1992 when metabotropic glutamate receptor type I (mGluR1a) was cloned by Nakanishi, et al., at least three splicing variants (mGluR1b, mGluR1c and mGluR1d) have been confirmed as mGluR1 variants (As to details, refer to Hermans, E. and Challiss, R. A., Biochemical J., 359:465–484, 2001). In all of those variants, the C-terminal region of mGluR1a becomes short, and their existence in nerve cells and glia cells has been confirmed. On the basis of such abundant receptor information, development for working drugs which are specific to each receptor has been extensively carried out. Even today new therapeutic drugs in the treatment of the above-mentioned diseases are being developed (As to details, refer to Barnard, E. A., Trends Pharmacol. Sci., 1997, May; 18(5):141–8; Schoepp, D. D., Conn. P. J., Trends Pharmacol. Sci., 1993, January; 14(1):13–10).
Nowadays, we have several pieces of knowledge that suggest physiological functions of the peripheral glutamate receptor (Berk, M., Plein, H., Ferreira, D., Clin. Neuropharmacol., 2001, May–June; 24(129–32; Karim, F., J. Neurosci. 2001, Jun. 1; 21(11):3771–9; Berk, M., Plein, H., Belsham, B., Life Sci. 2000;66(25):2427–32; Carlton, S. M., Goggeshall, R. E., Brain Res. 1999, Feb. 27; 820(1–2):63–70; Haxhij. M. A., Erokwu, B., Dreshaj, I. A., J. Auton. Nerv. Syst. 1997, Dec. 11; 67(3):192–9; Inagaki, N., FASEB J. 1995, May; 9(8):686–91; Erdo, S. L., Trends Pharamcol. Sci., 1991, November; 12(11):426–9; Aas, P., Tanso, R., Fonnum, F., Eur. J. Pharamacol. 1989, May 2; 164(1):93–102; Said, S. I., Dey, R. D., Dickman, K., Trends Pharmacol. Sci. 2001, July; 22(7):344–5; Skerry, T. M., Genever, P. G., Trends Pharamacol., Sci. 2001, April; 22(4):174–81). However, those peripheral glutamate receptors are expressed in peripheral nerves, smooth muscle and immune tissues. There has been no report for their expression in epithelium of tongue and digestive tract. In mammals including humans to maintain normal growth and health, it is necessary to orally take up required amounts of nutrients at a specific timing and excrete disposable matter. This is actually done by the digestive tract, which is a single tube consisting of oral cavity, stomach, small intestine and large intestine. The process of digestion and absorption is controlled by intrinsic intestinal neuroplexus and extrinsic cranial nerves.
The judgment as to whether or not to take a necessary nutrient is the result of brain integration of a signaling pathway that the individual is aware of taste with an autonomous signaling pathway that the individual is unaware of visceral sense. It is considered that salty taste (sodium, potassium, etc.) serves as a marker of minerals and is required for maintaining the osmotic pressure of the body fluid; sweetness (glucose) serves as a marker of carbohydrates and is required for supplementing energy; umami (sodium glutamate) serves as protein marker and is useful for supplementing energy and essential amino acids; and bitterness serves as a marker for toxic substances. That is, necessary nutrients are taken up relying on the tastes thereof. Then, if necessary amounts are ingested, satiation is determined by a series of intracerebral processes coming from the signal input to the solitary tract nucleus. Those signals are derived from activated vagus afferent fibers through nutrient sensors existing in the stomach, small intestine, and hepatoportal vein (Bray, G. A., Proc. Nutr. Soc., 2000;59:373–84; Bray G. A., Med. Clin. North. Am. 1989:73:29).
On the other hand, physiological studies on the mechanism for chemical sensation in the digestive tract have been performed for a long time. It is supposed that there are sensors that detect the content of the digestive tract (for the details, reference is made to Mei, N., J. Auton. Nerv. Syst., 1983;9:199–206; Mei, N., Lucchini, S., J. Auton, Nerv. Syst., 1992;41:15–8). The digestive chemosensory system includes a glucose sensor (Mei, N., J. Physiol. (Lond.) 1978, 282, 485-5-6), a temperature sensor (El Ouazzani, T., Mei, N., Exp. Brain Res. 1979;15;34:419–34), an osmotic pressure sensor (Mei, N., Garnier, L., J. Auton. Nerv. Syst., 1986;16:159–70), a pH sensor, an amino acid sensor (Mei, N., Physiol. Rev., 1985;65:211–37), and a stretch sensor (Barber, W. D., Burks, T. F., Gastroenterol Clin. North. Am. 1987; 16:521–4).
In particular, a sensor that recognizes glutamic acid was suggested by Niijima et al. from neural excitation that occurred when glutamic acid was administered in the digestive tract. In this experiment, the technique of recording neural discharge activity was used for the stomach branch and abdominal cavity branch of the vagus nerve. Those vagal branches control mainly the stomach and small intestine and responded to glutamic acid; therefore was assumed that there is a mechanism that recognizes this amino acid at the vagus nerve ending (Niijima, A., Physiol. Behav., 1991;49:1025–8).